title: The STIM1/Orai signaling machinery.
abstract: Ca(2+) influx via store-operated Ca(2+) release activated Ca(2+) (CRAC) channels represents a main signaling pathway for T-cell activation as well as mast-cell degranulation. The ER-located Ca(2+)-sensor, STIM1 and the Ca(2+)-selective ion pore, Orai1 in the membrane are sufficient to fully reconstitute CRAC currents. Their identification, but even more the recent structural resolution of both proteins by X-ray crystallography has substantially advanced the understanding of the activation mechanism of CRAC channels. In this review, we provide a detailed description of the STIM1/Orai1 signaling pathway thereby focusing on the critical domains mediating both, intra- as well as intermolecular interactions and on the ion permeation pathway. Based on the results of functional studies as well as the recently published crystal structures, we portray a mechanistic view of the steps in the CRAC channel signaling cascade ranging from STIM1 oligomerization over STIM1-Orai1 coupling to the ultimate Orai1 channel activation and permeation.
authors.affiliation: Institute of Biophysics; Johannes Kepler University Linz; Linz, Austria.
authors.forename: Marc
authors.initials: M
authors.lastname: Fahrner
authors.affiliation: Institute of Biophysics; Johannes Kepler University Linz; Linz, Austria.
authors.forename: Isabella
authors.initials: I
authors.lastname: Derler
authors.affiliation: Institute of Biophysics; Johannes Kepler University Linz; Linz, Austria.
authors.forename: Isaac
authors.initials: I
authors.lastname: Jardin
authors.affiliation: Institute of Biophysics; Johannes Kepler University Linz; Linz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Romanin
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D020013:Calcium Signaling; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D000071740:ORAI1 Protein; D011487:Protein Conformation; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1
keywords: CRAC channels; Orai; STIM; coiled-coil domain; immune system